Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease. Magnetic resonance imaging (MRI) has been widely used for the evaluation of MS. A common strategy is to employ T1- or T2-weighted fast spin echo or gradient echo sequences to detect the long T2 components in white matter of the brain. Although these sequences are highly sensitive in revealing macroscopic tissue abnormalities in the brain of patients with MS, they are not specific to the pathologic substrate of the MS lesion and have a limited prognostic role. MS is a disease that relatively specifically affects the myelin a lamellar membranous structure consisting of alternating protein and lipid layers which has an ultrashort T2*, and is not detected with conventional clinical sequences. Furthermore, recent studies have shown that Tysabri promoted regeneration and stabilization of damage done to the myelin sheath based on magnetization transfer (MT) imaging. However, MT is an indirect approach to assess myelin. It would be a major achievement to develop MRI techniques for direct morphological and quantitative imaging of myelin in white matter of the brain, and directly visualizing damage to it, as well as monitoring recovery during therapeutic treatment. We have developed Ultrashort Echo Time (UTE) sequences with minimum nominal TEs of 8 s that are 100-1000 times shorter than conventional TEs of several milliseconds or longer. These sequences make it possible to directly detect signal from myelin using clinical scanners. In this proposal, we will further develop UTE sequences for selective imaging of myelin, investigate contrast mechanisms including single adiabatic inversion recovery (SIR), dual adiabatic inversion recovery (DIR) and phase imaging, and develop quantitative UTE techniques to measure T1, T2*, phase and the proton density (PD) of myelin (Aim 1). We will then compare UTE and clinical sequences for morphological and quantitative evaluation of cadaveric human brains without (n=5) and with MS (n=5), and mice (n=20) using a standard cuprizone mouse model. We will compare and correlate the UTE and clinical measures with histopathology, and demonstrate that UTE can reliably assess dynamic changes in myelin during demyelination and remyelination induced by cuprizone treatment in mice (Aim 2). Finally we will apply the UTE techniques to evaluate MS in a longitudinal study of three groups of patients with relapsing-remitting MS (n=10), primary-progressive MS (n=10) and secondary-progressive MS (n=10) subject to Tysabri treatment (pre-, 6, 12 and 24 months post-treatment). A group of healthy volunteers (n=10) will also be recruited for comparison. We will compare UTE and clinical measures of cross-sectional and longitudinal changes in myelin with neurological assessment of expanded disability status scale (EDSS) (Aim 3). We expect that the UTE techniques will provide more specific and sensitive evaluation of the damage to myelin in MS patients subject to Tysabri treatment. The study is likely to improve the specificity of MRI for the diagnosis of MS, understanding of the natural history of the disease, and treatment monitoring.